Tissue engineering may be defined as the art of reconstructing mammalian tissues, both structurally and functionally (Hunziker, Osteoart. Cart., 10:432-465, 2002). In general, tissue engineering includes the delivery of a polymeric or ceramic scaffold that serves as an architectural support onto which cells may attach, proliferate, and synthesize new tissue to replace tissue losses due to disease, trauma or age. Innovations in orthopedic surgery include a vast array of biomaterials that provide mechanical stability, controlled release of therapeutic agents and a scaffold for cell anchorage.
Bone
Bone is a unique type of tissue made up of an inorganic mineral phase and cellular and extracellular matrix phases. Bone is a vital organ that undergoes modeling and remodeling wherein old bone is lost (resorption) and new bone is formed (formation/replacement). Although bone has an inherent capacity for repair and regeneration when damaged by disease or trauma, the renewed bone is often fragile and not weight bearing. Bone restoration or replacement is a viable consideration in indications including osteopenia, osteoporosis, bone tumors, spinal fusion, fractures and non-union fractures.
Bone formation may be enhanced either by recruiting osteoblasts, the bone forming cells, or by inhibiting recruitment or activity of osteoclasts, the bone resorbing cells. Osteoblasts and osteoclasts work together in a coordinated fashion to form and remodel bone tissue.
Many materials have been suggested for bone repair, specifically materials that avoid the harvesting problems associated with autologous matter and the health risks associated with allogenic material. Inorganic material such as calcium phosphate has been utilized as bone and dental fillers (reviewed in LeGeros, Clin Orthop 395:81-98, 2002). Apatite, a particulate calcium phosphate, is particularly appealing by virtue of the fact that it is the naturally occurring mineral component in bone and teeth. Bone apatite exhibits low crystallinity due to the presence of magnesium and carbonate (CO3) ions. Lack of crystallinity in apatites is associated with increased solubility in vivo. Hydroxyapatite, in contrast, exhibits high crystallinity and represents a small component of natural bone. Synthetic bone substitute materials comprising calcium phosphate or hydroxyapatite have been disclosed for use as bone grafts implants and cements.
U.S. Pat. No. 4,880,610 teaches a method for producing an injectable calcium phosphate mineral bone-like material using highly concentrated phosphoric acid, a calcium source and a neutralizing source, to which various additives may be incorporated, including sugars or proteins such as collagen, fibrinogen or elastin.
U.S. Pat. Nos. 5,650,176; 5,676,976 and 5,683,461 teach the synthesis of reactive amorphous calcium phosphates (ACP) and their use for promoting bone growth. U.S. Pat. No. 6,214,368 discloses an injectable bone substitute comprising the reactive ACP, an acidic second calcium phosphate material and liquid to form an injectable paste capable of hardening in vivo.
U.S. Pat. No. 5,281,265 discloses surgical cement comprising a calcium-based cementing component and a setting component capable of hardening in vivo. U.S. Pat. No. 6,375,935 discloses a flowable calcium phosphate composition that hardens in vivo.
U.S. Pat. No. 5,071,436 discloses a spongy bone substitute matrix consisting of glycosaminoglycans bonded to collagen together with hydroxyapatite. U.S. Pat. No. 6,118,043 discloses a porous bone replacement material consisting essentially of calcium minerals having an FGF polypeptide contained within.
U.S. Pat. Nos. 6,027,742 and 6,331,312 disclose a bioceramic composite capable of resorption in the body. The composition comprises resorbable poorly crystalline apatite (PCA) as a cement formed from amorphous calcium phosphate, a promoter and a biocompatible supplementary material selected from bioresorbable polymers or non-resorbable material, which impart a desirable biological, chemical or mechanical property. The composite is prepared by combining the PCA with the supplementary material.
U.S. Pat. No. 6,417,247 provides a composition comprising a polymer or polymer solution that forms a gel under controlled parameters and a ceramic matrix, the composition being fluid under non-physiological conditions and non fluid under physiological conditions. The compositions are prepared by mixing the ceramic component into a polymer solution.
EP 1208850A1 discloses a bone repair paste comprising an osteogenic promoter, a calcium component and a viscosity-increasing agent. The paste is prepared by admixing the three components to yield a sustained-release paste.
U.S. Pat. No. 6,231,607 discloses a novel bone substitute comprising hydroxy apatite and both α- and β-tricalcium phosphate (TCP), prepared by microwave irradiation and subsequent sintering. The intermediate powder material, resulting from microwave radiation, exhibits strong similarity to natural bone according to X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy analyses. Derivatives or a fluid composition comprising the dry powder were neither taught nor suggested in that disclosure.
Anti-Resorptive Agents
Anti-resorptive agents such as bisphosphonates have been widely used to prevent bone resorption and lower fracture risk in patients with osteoporosis and other diseases exhibiting osteolytic processes. Certain bone implants and cements comprising an anti-resorptive agent have been disclosed for filling bone voids and bonding prosthetic devices to bone. Denissen et al (Bone Miner. 25:123-134, 1994) describe the use of bisphosphonate-impregnated ceramic hydroxyapatite implants for the maintenance of bone mass following tooth extraction due to oral disease.
U.S. Pat. No. 5,733,564 teaches a method of treating endo-osteal materials by immersion in a bisphosphonate solution to enhance biocompatibility of prostheses. WO 00/47214 discloses anti-resorptive bone cements, comprising one or more anti-resorptive agents, preferably a bisphosphonate, useful for filling bone voids, bonding prosthetic devices to bone and for reconstructive bone surgery.
Existing bone graft implants, including pastes and cements, are prepared by admixing preformed calcium-based materials with a supplementary component such as a polymer or an anti-resorptive agent. In general, the calcium-based materials in the art, including synthetic apatites, are prepared using harsh conditions, e.g. low pH (phosphoric acid) or very high temperatures (>450° C.), thus precluding the generation of a composite incorporating such agents during the preparation steps. The art has not heretofore provided synthetic apatite composite material wherein a supplementary bioactive agent is included ab initio.
There remains an unmet medical need for a material having superior biological and physical properties for enhancing bone formation in orthopedic, periodontal and craniofacial indications.